Abstract | PURPOSE: EXPERIMENTAL DESIGN: Patients with solid tumors received i.v. KRN7000 (50-4,800 micro g/m(2)) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients. RESULTS: Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50-4,800 micro g/m(2)). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Valpha24+Vbeta11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels ( tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls (P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days. CONCLUSION: i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.
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Authors | Giuseppe Giaccone, Cornelis J A Punt, Yoshitaka Ando, Rita Ruijter, Nobusuke Nishi, Marlies Peters, B Mary E von Blomberg, Rik J Scheper, Hans J J van der Vliet, Alfons J M van den Eertwegh, Marja Roelvink, Jos Beijnen, Heinz Zwierzina, Herbert M Pinedo |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 8
Issue 12
Pg. 3702-9
(Dec 2002)
ISSN: 1078-0432 [Print] United States |
PMID | 12473579
(Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)
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Chemical References |
- Antigens, CD
- Antineoplastic Agents
- Galactosylceramides
- Ligands
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, Antigen, T-Cell, gamma-delta
- Interleukin-12
- Interferon-gamma
- Granulocyte-Macrophage Colony-Stimulating Factor
- KRN 7000
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Topics |
- Adult
- Aged
- Antigens, CD
(metabolism)
- Antineoplastic Agents
(adverse effects, pharmacokinetics, therapeutic use)
- Area Under Curve
- Cell Division
(drug effects)
- Cell Survival
(drug effects)
- Cytotoxicity, Immunologic
- Female
- Galactosylceramides
(adverse effects, pharmacokinetics, therapeutic use)
- Granulocyte-Macrophage Colony-Stimulating Factor
(metabolism)
- Humans
- Interferon-gamma
(metabolism)
- Interleukin-12
(metabolism)
- Killer Cells, Natural
(drug effects, immunology, metabolism)
- Ligands
- Lymphocyte Activation
(immunology)
- Male
- Maximum Tolerated Dose
- Middle Aged
- Neoplasms
(drug therapy, immunology)
- Receptors, Antigen, T-Cell, alpha-beta
(metabolism)
- Receptors, Antigen, T-Cell, gamma-delta
(analysis)
- T-Lymphocytes
(immunology)
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